(R)-Bicalutamide
(Synonyms: (R)-比卡鲁胺) 目录号 : GC61491
(R)-Bicalutamide是Bicalutamide的R型对映体。(R)-Bicalutamide是一种雄激素受体(AR)拮抗剂，具有抗肿瘤活性。(R)-Bicalutamide广泛用于前列腺癌的研究。
Cas No.:113299-40-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
(R)-Bicalutamide is the (R)-enantiomer of Bicalutamide . (R)-Bicalutamide is an androgen receptor (AR) antagonist, with antineoplastic activity. (R)-Bicalutamide is widely used for the research of prostate cancer[1][2].
Bicalutamide is available as a racemic mixture. The R isomer (R-bicalutamide) has an ≈30-fold higher binding affinity to the AR than the S isomer[1].(R)-bicalutamide (0.02-20 μM) reduces naÏve LNCaP cells survival in a dose-dependent[2]. Cell Proliferation Assay[2] Cell Line: LNCaP cells, LNCaP-Rbic cells
(R)-Bicalutamide (10 mg/kg; i.g.; daily; for 4 days) has antitumor efficacy in VCaP xenografts mice[3]. Animal Model: CD1 male nude (nu/nu) mice, with VCaP xenografts[3]
[1]. Hongli Liu, et al. Molecular mechanism of R-bicalutamide switching from androgen receptor antagonist to agonist induced by amino acid mutations using molecular dynamics simulations and free energy calculation. J Comput Aided Mol Des. 2016 Dec;30(12):1189-1200. [2]. Sara Pignatta, et al. Prolonged exposure to (R)-bicalutamide generates a LNCaP subclone with alteration of mitochondrial genome. Mol Cell Endocrinol. 2014 Jan 25;382(1):314-324. [3]. Anna Tesei, et al. Effect of Small Molecules Modulating Androgen Receptor (SARMs) in Human Prostate Cancer Models. PLoS One. 2013; 8(5): e62657.
| Cas No. | 113299-40-4 | SDF | |
| 别名 | (R)-比卡鲁胺 | ||
| Canonical SMILES | O=C(NC1=CC=C(C#N)C(C(F)(F)F)=C1)[C@@](C)(O)CS(=O)(C2=CC=C(F)C=C2)=O | ||
| 分子式 | C18H14F4N2O4S | 分子量 | 430.37 |
| 溶解度 | DMSO: 100 mg/mL (232.36 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3236 mL | 11.6179 mL | 23.2358 mL |
| 5 mM | 0.4647 mL | 2.3236 mL | 4.6472 mL |
| 10 mM | 0.2324 mL | 1.1618 mL | 2.3236 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Bicalutamide: clinical pharmacokinetics and metabolism
Clin Pharmacokinet 2004;43(13):855-78.PMID:15509184DOI:10.2165/00003088-200443130-00003.
Bicalutamide is a nonsteroidal pure antiandrogen given at a dosage of 150 mg once daily as monotherapy for the treatment of early (localised or locally advanced) nonmetastatic prostate cancer. It is used at a dosage of 50 mg once daily in combination with a luteinising hormone-releasing hormone analogue or surgical castration for the treatment of advanced prostate cancer. Bicalutamide is a racemate and its antiandrogenic activity resides almost exclusively in the (R)-enantiomer, with little, if any, activity in the (S)-enantiomer. (R)-Bicalutamide is slowly and saturably absorbed, but absorption is unaffected by food. It has a long plasma elimination half-life (1 week) and accumulates about 10-fold in plasma during daily administration. (S)-Bicalutamide is much more rapidly absorbed and cleared from plasma; steady-state concentrations (Css) of (R)-Bicalutamide are 100-fold higher than those of (S)-bicalutamide. Css increases linearly with doses up to 50 mg, but nonlinearly at higher doses, reaching a plateau above 300 mg. Css is higher in Japanese than in Caucasians, but no relationship with degree of renal impairment, bodyweight or age exists. Although mild-to-moderate hepatic impairment does not affect pharmacokinetics, there is evidence for slower elimination of (R)-Bicalutamide in subjects with severe hepatic impairment. Bicalutamide metabolites are excreted almost equally in urine and faeces with little or no unchanged drug excreted in urine; conversely, unchanged drug predominates in plasma. Bicalutamide in faeces is thought to arise from hydrolysis of bicalutamide glucuronide and from unabsorbed drug. Bicalutamide appears to be cleared almost exclusively by metabolism; this is largely mediated by cytochrome P450 (CYP) for (R)-Bicalutamide, but glucuronidation is the predominant metabolic route for (S)-bicalutamide. (S)-Bicalutamide is metabolised in vitro by CYP3A4, and it is probable that this isoenzyme is also responsible for the metabolism of (R)-Bicalutamide. In vitro data suggest that (R)-Bicalutamide has the potential to inhibit CYP3A4 and, to a lesser extent, CYP2C9, 2C19 and 2D6. However, using midazolam as a specific CYP3A4 marker, no clinically relevant inhibition is observed in vivo with bicalutamide 150mg. Although bicalutamide is a CYP inducer in laboratory animals, dosages < or = 150 mg/day have shown no evidence of enzyme induction in humans. Daily administration of bicalutamide increases circulating levels of gonadotrophins and sex hormones; although testosterone increases by up to 80%, concentrations in most patients remain within the normal range. Bicalutamide produces a dose-related decrease in prostate-specific antigen (PSA) at dosages < or = 150 mg/day. However, little relationship is observed between median PSA reduction and (R)-Bicalutamide Css.
Prolonged exposure to (R)-Bicalutamide generates a LNCaP subclone with alteration of mitochondrial genome
Mol Cell Endocrinol 2014 Jan 25;382(1):314-324.PMID:24397920DOI:10.1016/j.mce.2013.10.022.
Advanced prostate cancers, initially sensitive to androgen deprivation therapy, frequently progress to the castration-resistant prostate cancer phenotype (CRPC) through mechanisms not yet fully understood. In this study we investigated mitochondrial involvement in the establishment of refractoriness to hormone therapy. Two human prostate cancer cell lines were used, the parental LNCaP and the resistant LNCaP-Rbic, the latter generated after continuous exposure to 20 μM of (R)-Bicalutamide, the active enantiomer of Casodex®. We observed a significant decrease in mtDNA content and a lower expression of 8 mitochondria-encoded gene transcripts involved in respiratory chain complexes in both cell lines. We also found that (R)-Bicalutamide differentially modulated dynamin-related protein (Drp-1) expression in LNCaP and LNCaP-Rbic cells. These data seem to indicate that the androgen-independent phenotype in our experimental model was due, at least in part, to alterations in mitochondrial dynamics and to a breakdown in the Drp-1-mediated mitochondrial network.
A study of plasma bicalutamide concentrations in hemodialysis patients
Urol Int 2012;89(2):162-5.PMID:22868217DOI:10.1159/000339919.
Bicalutamide is an anti-androgen that is used worldwide to treat prostate cancer (CaP). However, there are no data on blood bicalutamide concentrations in hemodialysis (HD) patients with CaP. Therefore, we investigated the plasma levels of bicalutamide during the peridialysis period in this population. The study group included 5 HD patients with CaP who had been treated with bicalutamide (80 mg/day) for at least 3 months. Blood samples were taken during and between HD sessions and the plasma concentrations of the active R enantiomer (R-bicalutamide) were assessed using an HPLC assay. The plasma R-bicalutamide levels on the non-dialysis day were measured in 2 patients (patients 1 and 2) immediately before dosing and 8 and 24 h after dosing. These levels were 18,730, 19,090 and 19,420 ng/ml (patient 1), and 4,522, 4,581, and 5,296 ng/ml (patient 2), respectively. The mean plasma levels of R-bicalutamide in all 5 subjects just before HD, and 2 and 4 h after the start of HD were 8,726, 9,354 and 10,068 ng/ml, respectively. These results show that bicalutamide does not accumulate and is not diluted in the blood circulation of HD patients when given at the normal dosage used in the general population.
The effect of food on the pharmacokinetics of the bicalutamide ('Casodex') enantiomers
Biopharm Drug Dispos 1997 Aug;18(6):499-507.PMID:9312310DOI:10.1002/(sici)1099-081x(199708)18:6<499::aid-bdd37>3.0.co;2-j.
'Casodex' (bicalutamide) is an orally active, non-steroidal, pure antiandrogen; it is a racemate with antiandrogenic activity residing predominantly in the (R)-enantiomer. Healthy male volunteers (n = 15) were administered single oral doses of bicalutamide (50 mg) after food and after fasting as part of a three-treatment, three-period, randomized cross-over study, with a 9 week washout. After fasting, plasma concentrations of (R)-Bicalutamide were much higher than those of (S)-bicalutamide; the mean (R)-enantiomer Cmax (734 ng mL-1) was about nine times higher than the (S)-enantiomer value (84 ng mL-1). The corresponding tmax values were 19 and 3 h for (R)- and (S)-bicalutamide, respectively. Elimination of (R)-Bicalutamide from plasma was monoexponential and slow (t1/2 = 5.8 d). Elimination of (S)-bicalutamide was biphasic in some volunteers but monophasic in others (terminal t1/2 =1.2 d; n = 11). There was no significant effect of food on AUC, tmax, or t1/2 data for either enantiomer. The observed slightly higher values of Cmax for (R)-Bicalutamide (14%) and (S)-bicalutamide (19%), when dosing with food, achieved statistical significance. However, differences of this magnitude are unlikely to to be of any clinical relevance. These data indicate that 'Casodex' can be taken without reference to meal times; this may be of particular relevance for its indication in a disease of the elderly.
Enantiomer selective glucuronidation of the non-steroidal pure anti-androgen bicalutamide by human liver and kidney: role of the human UDP-glucuronosyltransferase (UGT)1A9 enzyme
Basic Clin Pharmacol Toxicol 2013 Aug;113(2):92-102.PMID:23527766DOI:10.1111/bcpt.12071.
Bicalutamide (Casodex(®) ) is a non-steroidal pure anti-androgen used in the treatment of localized prostate cancer. It is a racemate drug, and its activity resides in the (R)-enantiomer, with little in the (S)-enantiomer. A major metabolic pathway for bicalutamide is glucuronidation catalysed by UDP-glucuronosyltransferase (UGT) enzymes. While (S)bicalutamide is directly glucuronidated, (R)bicalutamide requires hydroxylation prior to glucuronidation. The contribution of human tissues and UGT isoforms in the metabolism of these enantiomers has not been extensively investigated. In this study, both (R) and/or (S)bicalutamide were converted into glucuronide (-G) derivatives after incubation of pure and racemic solutions with microsomal extracts from human liver and kidney. Intestinal microsomes exhibited only low reactivity with these substrates. Km values of liver and kidney samples for (S)bicalutamide glucuronidation were similar, and lower than values obtained with the (R)-enantiomer. Among the 16 human UGTs tested, UGT1A8 and UGT1A9 were able to form both (S) and (R)bicalutamide-G from pure or racemic substrates. UGT2B7 was also able to form (R)bicalutamide-G. Kinetic parameters of the recombinant UGT2B7, UGT1A8 and UGT1A9 enzymes support a predominant role of the UGT1A9 isoform in bicalutamide metabolism. Accordingly, (S)bicalutamide inhibited the ability of human liver and kidney microsomes to glucuronidate the UGT1A9 probe substrate, propofol. In conclusion, the present study provides the first comprehensive analysis of in vitro bicalutamide glucuronidation by human tissues and UGTs and identifies UGT1A9 as a major contributor for (R) and (S) glucuronidation in the human liver and kidney.